Featured Research

from universities, journals, and other organizations

Loss of enzyme reduces neural activity in Angelman syndrome

Date:

March 10, 2010

Source:

Harvard Medical School

Summary:

Angelman syndrome (AS) is a debilitating neurological disorder characterized by mental retardation and a high frequency of autism. Researchers have now found that the gene mutation underlying AS appears to affect the ability of neurons to communicate and to properly develop during the first few years of life, a time when brain activity is "rewired" by external stimuli.

Share This

Angelman Syndrome is a rare but serious genetic disorder that causes a constellation of developmental problems in affected children, including mental retardation, lack of speech, and in some cases, autism. Over a decade ago, researchers found that AS was caused by mutation in a single gene, but no one had been able to explain how this defect resulted in the debilitating neurological symptoms of the disease.

Related Articles

New work from Michael Greenberg, chair of the department of neurobiology at Harvard Medical School (HMS), provides insight into the mystery by showing that the lost enzyme, Ube3A, interacts with a key neuronal protein in order to control how environmental input shapes synaptic connections. In other words, loss of Ube3A interferes with the brain's ability to use environmental experience to fine-tune neuronal circuits, which could explain the devastating developmental deficits that occur in AS. This suggests new targets for treating Angelman syndrome. Currently, doctors can manage some AS symptoms, but there is no treatment for the core features.

What's more, the Ube3A gene is also mutated in some cases of autism, raising the possibility that these findings may also explain some of the problems that occur in autism spectrum disorders, which are 100 times more common than AS.

"With this work, we've gone from a place where we could only imagine how Ube3A might work, to being able to think about possibilities for therapeutic intervention in a disorder where until very recently there was little that could be done," says Greenberg, Nathan Marsh Pusey professor of neurobiology at HMS.

These findings are published in the March 5 issue of Cell.

During the first few years of life, brain activity is "rewired" by external stimuli . This tweaking of neuronal connections is critical to establish normal neurological function, and is thought to go awry in a number of developmental disorders that lead to mental retardation or other cognitive problems. The new work suggests that Ube3A is a key regulator in this process, and ties the loss of Ube3A to a specific change in synaptic function.

Under normal conditions, the Ube3A enzyme tags cellular proteins for destruction. Co-ead author Paul Greer, a postdoctoral fellow in Greenberg's lab identified the synaptic protein Arc as one of Ube3A's targets. Arc's primary function is to decrease neuronal signaling. However, with a mutated Ube3A, Arc accumulates to higher than normal levels, which causes an abnormal lowering of neuronal signaling, leading to impaired neuronal communication and synaptic development.

The Arc connection has revealed surprising links to other disorders, Greenberg says. In Fragile X syndrome, a major form of inherited mental retardation, neurons also have an over-abundance of Arc protein. Although the excess Arc occurs through a different mechanism independent of Ube3A, the two diseases seem to converge on a common synaptic defect. That means new treatments now under study for Fragile X may someday be useful for Angelman Syndrome, Greenberg says.

The work may also suggest additional therapeutic targets for AS. As part of the study, the researchers identified several proteins regulated by Ube3A in addition to Arc, some of which might be involved in creating the complex features of AS. "It could be that affecting Arc levels may be useful for some of the symptoms of AS, while modulating other targets will be useful for others," Greer says. "We are hoping to identify many substrates upon which Ube3a is acting, and one can imagine doing targeted therapeutics on several of them."

This research was funded by the National Science Foundation, National Institutes of Health, Angelman Syndrome Foundation.

Story Source:

The above story is based on materials provided by Harvard Medical School. The original article was written by Pat McCaffrey. Note: Materials may be edited for content and length.

More From ScienceDaily

More Health & Medicine News

Featured Research

Mar. 3, 2015 — New assays can detect malaria parasites in human blood at very low levels and might be helpful in the campaign to eradicate malaria, reports a new study. An international team led by Ingrid Felger, ... full story

Mar. 3, 2015 — Adults over the age of 30 only catch flu about twice a decade, a new study suggests. So, while it may feel like more, flu-like illness can be caused by many pathogens, making it difficult to assess ... full story

Mar. 3, 2015 — No significant change in home habits of smokers have been observed in the aftermath of a ban on smoking in public spaces, researchers report. Greater inspiration to kick the habit likely comes from ... full story

Mar. 3, 2015 — Heart function has been associated with the development of dementia and Alzheimer's disease through a new study. Participants with decreased heart function, measured by cardiac index, were two to ... full story

Mar. 3, 2015 — Children of recently separated or divorced families are likelier to drink sugar-sweetened beverages than children in families where the parents are married, putting them at higher risk for obesity ... full story

Mar. 3, 2015 — Gastric bypass and similar stomach-shrinking surgeries are a popular option for obese patients looking to lose weight or treat type 2 diabetes. While the surgeries have been linked to a decreased ... full story

Mar. 3, 2015 — Most people consume more salt than they need and therefore have a higher risk of heart disease and stroke, which are the two leading causes of death worldwide. But a new study reveals that dietary ... full story

Mar. 3, 2015 — Twice as many children born to mothers who took antibiotics during pregnancy were diagnosed with asthma by age 3 than children born to mothers who didn’t take prenatal antibiotics, a new study has ... full story

Mar. 3, 2015 — Although sedatives are often administered before surgery, a randomized trial finds that among patients undergoing elective surgery under general anesthesia, receiving the sedative lorazepam before ... full story

Featured Videos

Mom Triumphs Over Tragedy, Helps Other Families

AP (Mar. 3, 2015) — After her son, Dax, died from a rare form of leukemia, Julie Locke decided to give back to the doctors at St. Jude Children&apos;s Research Hospital who tried to save his life. She raised $1.6M to help other patients and their families. (March 3)
Video provided by AP

Looted and Leaking, South Sudan's Oil Wells Pose Health Risk

AFP (Mar. 3, 2015) — Thick black puddles and a looted, leaking ruin are all that remain of the Thar Jath oil treatment facility, once a crucial part of South Sudan&apos;s mainstay industry. Duration: 01:13
Video provided by AFP

Woman Convicted of Poisoning Son

AP (Mar. 3, 2015) — A woman who blogged for years about her son&apos;s constant health woes was convicted Monday of poisoning him to death by force-feeding heavy concentrations of sodium through his stomach tube. (March 3)
Video provided by AP

Related Stories

Jan. 9, 2014 — A team of scientists has discovered the structure of the active form of E6-associated protein (E6AP), an enzyme that acts as a master regulator, controlling functions like the ability of nerve cells ... full story

Oct. 23, 2013 — Researchers describe a major reason why current medications only moderately alleviate Fragile X symptoms. His team discovered that three specific drugs affect three different kinds of ... full story

Jan. 14, 2013 — A new finding in neuroscience for the first time points to a developmental mechanism linking the disease-causing mutation in an autism-related disorder, Timothy syndrome, and observed defects in ... full story

Nov. 12, 2012 — New research from the University of North Carolina provides a neurological justification for this therapeutic approach, but researchers caution there could be unanticipated ... full story

ScienceDaily features breaking news and videos about the latest discoveries in health, technology, the environment, and more -- from major news services and leading universities, scientific journals, and research organizations.